Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells.
Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells.
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DOI：
10.1038/s41467-021-23329-z
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发表时间：
2021-05-26
影响因子：
16.6
通讯作者：
Keller G
中科院分区：
文献类型：
--
作者：
Funakoshi S;Fernandes I;Mastikhina O;Wilkinson D;Tran T;Dhahri W;Mazine A;Yang D;Burnett B;Lee J;Protze S;Bader GD;Nunes SS;Laflamme M;Keller G
构成成人心脏心室壁的致密心肌细胞代表了用于建模和治疗心血管疾病的重要治疗目标群体。在这里，我们建立了一个分化策略，促进从人多能干细胞（hPSC）的致密心室心肌细胞的规格，增殖和成熟。在这些条件下产生的心肌细胞显示出使用脂肪酸作为能量来源的能力、高线粒体质量、明确的肌节结构和增强的收缩力。这些心室细胞在体外受到病理刺激时发生代谢变化，表明与心力衰竭相关，并且发现在移植到梗死大鼠心脏后，这些心室细胞产生的移植物由比来自未成熟心肌细胞的细胞更成熟的细胞组成。hPSC衍生的心房心肌细胞也对本研究中鉴定的成熟线索作出反应，表明该方法广泛适用于心脏的不同亚型。总的来说，这些发现突出了概括胚胎和出生后发育的关键方面以从hPSC产生治疗相关细胞类型的能力。心室肌细胞由小梁型和致密型两种亚群组成。在这里，作者描述了从人多能干细胞中产生结构、代谢和功能成熟的致密心室心肌细胞以及成熟的心房心肌细胞。
Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs. Cardiomyocytes of heart ventricles consist of subpopulations of trabecular and compact subtypes. Here the authors describe the generation of structurally, metabolically and functionally mature compact ventricular cardiomyocytes as well as mature atrial cardiomyocytes from human pluripotent stem cells.
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